Genetic risk factors for Mesoamerican nephropathy

Authors

• David J. Friedman, Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, MA 02215.
• Dominick A. Leone, Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118.
• Juan José Amador, Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118.
• Joseph Kupferman, Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, MA 02215.
• Lauren J. Francey, Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, MA 02215.
• Damaris Lopez-Pilarte, Centro Medico del Pacifico, Masaya, Nicaragua 41000.
• Jorge Lau, Especialistas en Medicina Interna, Chichigalpa, Nicaragua 26100.
• Iris Delgado, Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118.
• W Katherine Yih, Harvard Medical School, Boston, MA 02215.
• Alejandro Salinas, Especialistas en Medicina Interna, Chichigalpa, Nicaragua 26100.
• Minxian Wang, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142.
• Giulio Genovese, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142.
• Shrijal Shah, Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, MA 02215.
• Jessica Kelly, Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, MA 02215.
• Calum F. Tattersfield, Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, MA 02215.
• Nathan H. Raines, Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, MA 02215.
• Magaly Amador, Centro Medico del Pacifico, Masaya, Nicaragua 41000.
• Leny Dias, Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, MA 02215.
• Achilleas Pitsillides, Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118.
• Oriana Ramirez-Rubio, Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118.
• Alda G. Amador, Centro Medico del Pacifico, Masaya, Nicaragua 41000.
• Marissa Cortopassi, Endocrinology Division, Beth Israel Deaconess Medical Center, Boston, MA 02215.
• Katie M. Applebaum, Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC 20052.
• Seth L. Alper, Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, MA 02215.
• Alex S. Banks, Harvard Medical School, Boston, MA 02215.
• Michael D. McClean, Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118.
• Jessica H. Leibler, Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118.
• Madeleine K. Scammell, Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118.
• Josée Dupuis, Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118.
• Daniel R. Brooks, Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118.

Document Type

Journal Article

Publication Date

12-3-2024

Journal

Proceedings of the National Academy of Sciences of the United States of America

Volume

121

Issue

49

DOI

10.1073/pnas.2404848121

Keywords

Mesoamerican; OPCML; genetics; kidney disease

Abstract

Mesoamerican nephropathy (MeN) is a progressive kidney disease found on the Pacific coast of Central America primarily in young male agricultural workers without typical kidney disease risk factors. While it is generally accepted that environmental exposures contribute to MeN, we hypothesized that there was also an important genetic component. We performed a genome-wide association study comparing individuals with MeN versus individuals with normal kidney function. We found that Native American ancestry was strongly associated with increased risk of MeN. We also identified candidate variants in the OPCML gene, which encodes a protein that binds opioid receptors, that were associated with ~sixfold reduced odds of MeN (allele frequency 0.029 in controls and 0.005 in cases, OR = 0.16; P = 4 × 10). Sugarcane workers with the protective OPCML variants had markedly increased urine osmolality suggesting greater ability to defend against hypovolemia. Experiments with Opcml knock-out mice revealed roles for OPCML in fluid balance and temperature regulation consistent with our findings in humans. Our data suggest that heritable differential sensitivity to heat stress and dehydration contributes to high rates of kidney disease in Central America.

APA Citation

Friedman, David J.; Leone, Dominick A.; Amador, Juan José; Kupferman, Joseph; Francey, Lauren J.; Lopez-Pilarte, Damaris; Lau, Jorge; Delgado, Iris; Yih, W Katherine; Salinas, Alejandro; Wang, Minxian; Genovese, Giulio; Shah, Shrijal; Kelly, Jessica; Tattersfield, Calum F.; Raines, Nathan H.; Amador, Magaly; Dias, Leny; Pitsillides, Achilleas; Ramirez-Rubio, Oriana; Amador, Alda G.; Cortopassi, Marissa; Applebaum, Katie M.; Alper, Seth L.; Banks, Alex S.; McClean, Michael D.; Leibler, Jessica H.; Scammell, Madeleine K.; Dupuis, Josée; and Brooks, Daniel R., "Genetic risk factors for Mesoamerican nephropathy" (2024). GW Authored Works. Paper 6213.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/6213

Department

Environmental and Occupational Health